Finding Answers About Large Congenital Melanocytic Nevi

By , Staff Writer, Nevus Outreach

In hospitals around the world, physicians and researchers are pondering how some cells in a developing embryo grow into a large congenital melanocytic nevus (CMN). Most especially, they wonder what they can do about it, when a child is born with one.

Searching for Treatment Possibilities

At the Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Miguel Reyes-Múgica, MD, has established a new research group with full-time PhD scientists and student trainees, dedicated to nevus research. Reyes is Chief of Pathology and Director of Laboratories at Children’s Hospital of Pittsburgh.

While he is approaching this work from several angles, the major question he wants to address is this: Once a patient with a nevus is born, what treatments other than surgery can we develop to improve his or her condition?

Harnessing Molecules

Reyes is building on the knowledge that CMN derive from a temporary cell type present in the one- to two-month human embryo, called the neural crest.

“Essentially, we are trying to target the biological processes that control the transformation of one tissue into another. In this case, we are looking at the transformation of neural crest cells into a congenital nevus,” Reyes says.

“This is a very complex process, which includes a phenomenon called epithelial-mesenchymal (EM) transition,” he says. “We have identified a potential target molecule that appears to control not only EM transition, but also another biological process called senescence. Senescence has to do with biological aging and death.

“If neural crest cells are going to transform into a nevus cell, and we can harness this molecule to control the process triggering this change, we may be able to stop it,” he says.

Reyes and his colleagues are working with a model of stem cells similar to neural crest cells and hope to develop studies with laboratory animals. Specifically, Reyes wants to see if stem cells programmed to form melanocytes (pigment producing cells) can be stopped or induced to going into senescence. This is a primary angle of his work.

Looking Toward the Future

“The mainstay of treatment today is surgery. It is still relatively early, but eventually we hope to develop drug therapy by which the transition of primitive cells can be controlled and stopped — or even reversed. It is possible that knowing how satellite (smaller) nevi develop after birth, we could arrest their development,” says Reyes.

“That is our aim. We have high hopes for this, but we are early in the process. Importantly, findings from nevus research will be applicable to cancer as well.”

Reyes is also developing a tissue repository, where excess tissue from patients undergoing surgery for removal of congenital moles — especially giant nevi — can be stored. This tissue can then be provided to researchers carrying out additional studies to further increase our understanding of many different angles in nevus development.

Looking for the Cause of CMN

Dr. Heather Etchevers with the Nevus Outreach blood samples.

Across the Atlantic in a lab not far from the Mediterranean Sea, Heather Etchevers, PhD, is on the threshold of what she too hopes will be important nevus-related discoveries.

“Specifically, we want to know why someone develops a CMN? What is different in them from their parents and everybody else who doesn’t have a nevus?” asks Etchevers, a molecular embryologist at the French National Institute of Health and Medical Research (INSERM), in Marseilles.

”What we think is happening is that a predisposition may be inheritable from one generation to the next — even though neither parent had a nevus. Whatever is inherited just gives you the possibility to develop a CMN.

“So we are looking for two things: First, what is inborn that favors the development of a nevus? Second, what happens after fertilization — but before birth — that stimulates the onset of a CMN?”

In other words, EM transition may be the biological process that causes the nevus to develop. But what triggers this transition? Etchevers hopes to identify one or more factors that actually cock the trigger, fueling this molecular event.

Putting Your Blood to Work

“Miguel and I talked about this a lot and we agree that we need nevus tissue for research. But we need blood samples, too, as blood is representative of the whole body. Blood is a lot easier to obtain than skin, too,” she adds.

Etchevers attended the Nevus Outreach conference last July with her daughter Marjorie, who was born with a congenital nevus in 1999. Etchevers returned to France as the appointed guardian of the 123 blood samples collected at what she says was an inspirational meeting.

A number of preliminary steps have been taken already to begin processing the blood. First, technicians at the DNA “bank” at the Necker Children’s Hospital in Paris, where the blood was sent, extracted the white blood cells from the liquid blood. They stored these cells as small pinkish pellets in little-finger size vials that Etchevers brought back to her lab in Marseille to extract the DNA.

Pure DNA

Technicians at the bank do routinely extract DNA from each donor's white blood cells on automated machines, says Etchevers. But she will conduct the extractions by hand, instead. While tedious, her method will yield the cleaner, higher quality DNA desirable for the analyses she has in mind. It will also make it possible for other researchers to use any technique for future projects.

A necessary first step in assessing DNA quality for future experiments is to see how degraded it was by the isolation procedure. To this purpose, Etchevers places liquid DNA samples in an electric field to separate long strands from shorter, broken ones. This process verifies that enough of the former have been preserved.

Once the DNA is purified and its quality checked, Etchevers and her collaborators will begin looking for clues to unravel the mystery of how a congenital nevus forms.

A Question of Timing

“We are talking about a malformation of the skin that happens before birth,” says Etchevers.

“During the development of the child, who is going to be born with a nevus, there was a time when that child didn’t have it yet.”

It’s a question of timing. The earlier that a molecular change in the DNA of neural crest or skin happens, the bigger the nevus might be.

The trigger for change may be a fairly common event after birth, since almost everyone on earth develops a nevus (mole) during his or her lifetime. CMN are a little different from these moles, but investigators believe the process is similar and are looking to prove it.

Etchevers and Reyes are hoping to find out how moles or large CMN develop at the molecular level. With this understanding, they want to develop in vitro or animal models that repeat the process. Thus, drugs eventually may be designed to treat CMN patients without surgery. In addition, this level of understanding should cast light on how other CMN-related conditions such as various tumors or neurocutaneous melanocytosis may develop.

Advancing Research Today

Etchevers and Reyes are optimistic that they will get some answers. This is because lately a serious group of people — from clinicians and researchers to families with patients affected by large nevi — has converged to push for research. Furthermore, the right kind of management and leadership is fostering this growing network, too, and making things happen — just like the inspirational blood drive from last summer.

Both as a mother of a child with a nevus, and as a researcher, Etchevers says, “Thank you. All of you who have donated blood have done something amazing. But please be patient. Getting [something useful] back to the patient can take years, which I know is frustrating. But, for sure, it will happen. Guaranteed.

“2011 and 2012 are going to be great years,” Etchevers predicts. “We are going to transform the landscape of what we know. To advance nevus research, it's no longer: 'If we don't do it, it won't get done.' We all are doing it together and it is getting done!”